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Product Details of [ 1878-67-7 ]

CAS No. :1878-67-7 MDL No. :MFCD00004330
Formula : C8H7BrO2 Boiling Point : -
Linear Structure Formula :- InChI Key :KYNNBXCGXUOREX-UHFFFAOYSA-N
M.W : 215.04 Pubchem ID :74653
Synonyms :
Chemical Name :2-(3-Bromophenyl)acetic acid

Calculated chemistry of [ 1878-67-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 45.69
TPSA : 37.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.93 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.64
Log Po/w (XLOGP3) : 2.37
Log Po/w (WLOGP) : 2.08
Log Po/w (MLOGP) : 2.4
Log Po/w (SILICOS-IT) : 2.21
Consensus Log Po/w : 2.14

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.94
Solubility : 0.248 mg/ml ; 0.00115 mol/l
Class : Soluble
Log S (Ali) : -2.79
Solubility : 0.346 mg/ml ; 0.00161 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.04
Solubility : 0.198 mg/ml ; 0.000923 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.55

Safety of [ 1878-67-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1878-67-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 1878-67-7 ]
  • Downstream synthetic route of [ 1878-67-7 ]

[ 1878-67-7 ] Synthesis Path-Upstream   1~45

  • 1
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Reference: [1] Journal of Organic Chemistry, 1970, vol. 35, p. 2746 - 2750
  • 2
  • [ 1878-67-7 ]
  • [ 74-88-4 ]
  • [ 53086-52-5 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.25 h;
Stage #2: at -78 - 20℃;
A solution of LDA in THF/n-heptane/ethylbenzene (1.8M, 23.25 mL, 41.85 mmol) is cooled down to -78°C and added a solution of 3-bromophenylacetic acid [3 g, 13.95 mmol, Intermediate (68)] in THF (7 mL) dropwise over 15 minutes. The mixture is stirred for 1 h at -78°C and treated dropwise with methyl iodide (6.34 g, 44.64 mmol) over 15 minutes. The reaction mixture is warmed up to room temperature and after stirring overnight, the mixture is quenched with 2N hydrochloric acid and concentrated to remove THF. The residue is diluted with ether, washed twice with 2 N hydrochloric acid (20 mL) and extracted twice with 10percent sodium hydroxide (20 mL). The combined sodium hydroxide extracts are acidified with 6 N hydrochloric acid to pH=l and extracted three times with ether (50 mL). Combined organic extracts are washed with brine, dried over sodium sulfate and concentrated to obtain 2-f3-bromo-phenyl)-propionic acid [3 g, 100percent, Intermediate (69)] as a solid, which is used without further purification. LC/MS: 229 (M+H).
100%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.25 h;
Stage #2: at -78 - 20℃;
A solution of LDA in THF/n-heptane/ethylbenzene (1.8M, 23.25 mL, 41.85 mmol) is cooled down to -78°C and added a solution of 3-bromophenylacetic acid [3 g, 13.95 mmol, Intermediate (68)] in THF (7 mL) dropwise over 15 minutes. The mixture is stirred for 1 h at -78°C and treated dropwise with methyl iodide (6.34 g, 44.64 mmol) over 15 minutes. The reaction mixture is warmed up to room temperature and after stirring overnight, the mixture is quenched with 2N hydrochloric acid and concentrated to remove THF. The residue is diluted with ether, washed twice with 2 N hydrochloric acid (20 mL) and extracted twice with 10percent sodium hydroxide (20 mL). The combined sodium hydroxide extracts are acidified with 6 N hydrochloric acid to pH=l and extracted three times with ether (50 mL). Combined organic extracts are washed with brine, dried over sodium sulfate and concentrated to obtain 2-f3-bromo-phenyl)-propionic acid [3 g, 100percent, Intermediate (69)] as a solid, which is used without further purification. LC/MS: 229 (M+H).
84%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexanes at 20℃; for 0.25 h;
Stage #2: at 20℃; for 0.25 h;
Stage #3: at 20℃; for 0.25 h;
To a solution of diisopropylamine (0.97 g, 9.6 mmol) in THF (20 mL) at room temperature was added n-butyl lithium (2.5 N in hexane, 4 mL, 10 mmol) and the resulting solution was stirred at room temperature for 15 minutes. To above solution was added a solution of 3-bromophenylacetic acid (1.0 g, 4.6 mmol) in THF (10 mL) dropwise at room temperature and the stirring was continued for another 15 minutes. Methyl iodide (1.49 g, 10.5 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. Satuated sodium chloride (30 mL) was added and the aqueous phase was adjusted to pH 5 by addition of hydrochloric acid (1 N). The resulting mixture was extracted with ethyl acetate (20 mL.x.3) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of formic acid and methanol in dichloromethane to afford 2-(3-bromo-phenyl)-propionic acid (890 mg, 84percent) as a white solid. MS: m/z 229 (M+H+).
82%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran; toluene at 20℃; for 0.333333 h;
Stage #2: for 0.166667 h;
General procedure: Step 1. To a solution of 3-bromophenylacetic acid (1.30 g, 6 mmol) (azeotroped with toluene) in 2 mL of dry toluene was added sodium bis(trimethylsilyl)amide (14 mL of 1N solution in THF, 14 mmol). After stirring at room temperature for 20 min, methyl iodide (0.9 g, 7 mmol) was added dropwise. After 10 min, the reaction was quenched with 2 N HCl to pH = 2, extracted with EtOAc, dried over Na2SO4, filtered and evaporated to dryness. Flash column (SiO2, DCM to DCM/EtOAc = 10:1 to 4:1 to 2:1) gave crude 2-(3-bromophenyl)propanoic acid (1.13 g, 82percent yield) as colorless oil.

Reference: [1] Patent: WO2008/39882, 2008, A1, . Location in patent: Page/Page column 171
[2] Patent: WO2008/39882, 2008, A1, . Location in patent: Page/Page column 171
[3] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 110-111
[4] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6447 - 6454
[5] Patent: WO2016/193939, 2016, A1, . Location in patent: Page/Page column 41
  • 3
  • [ 201230-82-2 ]
  • [ 932-77-4 ]
  • [ 1878-67-7 ]
YieldReaction ConditionsOperation in experiment
79%
Stage #1: With C28H22CoN4O6 In butan-1-ol at 60℃; for 2 h; Glovebox; High pressure; Green chemistry
Stage #2: With tetra-(n-butyl)ammonium iodide; sodium hydroxide In butan-1-ol at 60℃; for 22 h; Glovebox; High pressure; Green chemistry
General procedure: A 100 mL reactor equipped with Teflon-coated magnetic stir bars was charged with n-Butyl alcohol (20 mL) and the catalyst (0.5 mmol). The reactor was then taken out of the glove box and pressured with carbon monoxide (1 atm). The mixture was stirred 2 h at 60 °C, cooled to ambient temperature and slowly vented. After benzyl chloride (10 mmol), NaOH (15 mL, 15percent), and TBAI (0.25 mmol) were added, the reactor was sealed and the reaction mixtures were stirred for 22 h at 60 °C under carbon monoxide (1 atm). After the reaction, the water phase was detached and washing the organic phase three times with H2O (3×5 mL), the combined water layer was washed with Et2O, then the resulting solution was cooled to 0 °C and adjusted to pH=1–2 with HCl (6 mol/L). The product was filtered, dried in RT, and then recrystallized.
Reference: [1] Tetrahedron, 2013, vol. 69, # 35, p. 7264 - 7268
  • 4
  • [ 2142-63-4 ]
  • [ 1878-67-7 ]
YieldReaction ConditionsOperation in experiment
92.3%
Stage #1: for 14 h; Reflux
Stage #2: With sulfuric acid; acetic acid In water at 20 - 30℃; for 6 h; Reflux
In 1000ml three-necked flask of sublimed sulfur were added 24g (0.75mol), 100g3- bromoacetophenone (0.5mol) and 65.4g (0.75mol) morpholine was stirred at reflux for 14 hours. Cooling to 20 ~ 30 , stirring joined by glacial acetic acid 260ml, 75ml and 52ml distilled water mixed with concentrated sulfuric acid solution dubbed refluxing was continued for 6 hours. The reaction mixture was poured into ice water, stirring to brown solid precipitated was filtered. The solid was dissolved 300ml20percent aqueous sodium hydroxide solution and filtered. The filtrate was placed in an ice bath, 2mol / L of hydrochloric acid to adjust pH = 1 ~ 2, crystallization, filtration, 60 dried to give 99.2g of yellow solid 2, a yield of 92.3percent.
Reference: [1] Patent: CN105348195, 2016, A, . Location in patent: Paragraph 0005; 0015
  • 5
  • [ 31938-07-5 ]
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3018 - 3022
[2] Journal fuer Praktische Chemie (Leipzig), 1932, vol. <2> 133, p. 331,346
[3] Journal of the Chemical Society, 1948, p. 1251,1254
[4] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1880, p. 481
  • 6
  • [ 14062-30-7 ]
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YieldReaction ConditionsOperation in experiment
4.1 g With lithium hydroxide In tetrahydrofuran; water at 20℃; for 1 h; Under room temperature, will ethyl 3-bromophenylacetate (5.0 g, 20.6 mmol) and LiOH (1.0 g, 41.8 mmol) added THF (30 ml) and water (20 ml) in the mixed solution. Under room temperature, the resultant reaction mixture of 1 hour. Using 2N pH=2. HCl solution to adjust the The resulting mixture is extracted with ethyl acetate. The resulting organic phase is concentrated to obtain 4.1 g of white solid.
Reference: [1] Patent: CN105384739, 2016, A, . Location in patent: Paragraph 0312; 0313; 0314
  • 7
  • [ 124-38-9 ]
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Reference: [1] Chemical Science, 2018, vol. 9, # 21, p. 4873 - 4878
  • 8
  • [ 2039-86-3 ]
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Reference: [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 12, p. 2132 - 2141
[2] RSC Advances, 2016, vol. 6, # 8, p. 6719 - 6723
  • 9
  • [ 591-18-4 ]
  • [ 64-19-7 ]
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Reference: [1] ChemCatChem, 2014, vol. 6, # 6, p. 1589 - 1593
  • 10
  • [ 7023-79-2 ]
  • [ 1878-67-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1723 - 1727
  • 11
  • [ 585-76-2 ]
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1723 - 1727
  • 12
  • [ 591-19-5 ]
  • [ 1878-67-7 ]
Reference: [1] Patent: CN107417509, 2017, A,
  • 13
  • [ 66955-75-7 ]
  • [ 1878-67-7 ]
Reference: [1] Chemische Berichte, 1882, vol. 15, p. 838[2] Chemische Berichte, 1882, vol. 15, p. 3060
  • 14
  • [ 328002-25-1 ]
  • [ 1878-67-7 ]
Reference: [1] Journal of the Chemical Society, 1948, p. 1251,1254
  • 15
  • [ 3544-25-0 ]
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Reference: [1] Chemische Berichte, 1882, vol. 15, p. 838[2] Chemische Berichte, 1882, vol. 15, p. 3060
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  • [ 25025-06-3 ]
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Reference: [1] Chemische Berichte, 1882, vol. 15, p. 838[2] Chemische Berichte, 1882, vol. 15, p. 3060
  • 17
  • [ 501357-70-6 ]
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Reference: [1] Chemische Berichte, 1882, vol. 15, p. 838[2] Chemische Berichte, 1882, vol. 15, p. 3060
  • 18
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  • [ 823-78-9 ]
Reference: [1] Organic Letters, 2017, vol. 19, # 7, p. 1634 - 1637
  • 19
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  • [ 40422-70-6 ]
Reference: [1] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 3, p. 183 - 188
  • 20
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  • [ 14062-25-0 ]
  • [ 14062-30-7 ]
Reference: [1] Patent: US5489584, 1996, A,
  • 21
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  • [ 2084-13-1 ]
Reference: [1] Patent: WO2013/52110, 2013, A1,
  • 22
  • [ 1878-67-7 ]
  • [ 28229-69-8 ]
YieldReaction ConditionsOperation in experiment
79%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 20 h;
Stage #2: With water In tetrahydrofuran
BH3-Me2S (7 ml_ of a 2M solution in THF, 14.0 mmol) was added to a cold (0 0C) solution of 3-bromophenylacetic acid (2.00 g, 9.3 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 20 hours and re-cooled to 0 0C. Water (10 ml.) was added dropwise. The organic layer was separated, washed with brine (20 mL), dried (MgSO4), filtered and concentrated under reduced pressure to leave a colourless oil. Purification by column chromatography (50 percent EtOAc in heptane) afforded the title compound as a colourless oil (1.47 g, 79 percent yield). m/z 224/226 [M+H]+. 1H NMR (300 MHz, CDCI3) 7.41-7.35 (2H, m), 7.23-7.16 (2H, m), 3.87 (2H, t, J=6.5 Hz), 2.86 (2H, t, J=6.5 Hz).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3018 - 3022
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 3, p. 183 - 188
[3] Patent: WO2008/53136, 2008, A1, . Location in patent: Page/Page column 38
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2882 - 2891
[5] Journal of Medicinal Chemistry, 1998, vol. 41, # 3, p. 358 - 378
[6] Journal of Medicinal Chemistry, 2006, vol. 49, # 5, p. 1562 - 1575
[7] Patent: WO2006/11631, 2006, A2, . Location in patent: Page/Page column 67-68
[8] Patent: US6316466, 2001, B1,
[9] Patent: US5827868, 1998, A,
[10] Patent: US5087635, 1992, A,
[11] Patent: WO2004/67521, 2004, A1, . Location in patent: Page 228-229
[12] Journal of the American Chemical Society, 2010, vol. 132, # 12, p. 4076 - 4077
[13] Patent: WO2007/69986, 2007, A1, . Location in patent: Page/Page column 89
[14] Journal of the American Chemical Society, 2011, vol. 133, # 43, p. 17142 - 17145
[15] Patent: US2014/57914, 2014, A1, . Location in patent: Paragraph 0356-0357
[16] Chemistry - A European Journal, 2014, vol. 20, # 47, p. 15325 - 15329
[17] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
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YieldReaction ConditionsOperation in experiment
93% With sulfuric acid In ethanolReflux Step A: Ethyl 2-(3-bromophenyl acetate (35i-b) 3-Bromophenylacetic acid, 35i-a, (50g, 0.23mol) was dissolved in ethanol (250 mL) and sulfuric acid was added drop-wise. The mixture was heated to reflux and stirred overnight. The solution was adjusted to about a pH of 7-8 with sodium hydroxide solution and concentrated in vacuo. The water phase was extracted with ethyl atetate (3 x 150 mL) and the combined organics was washed with brine (50 mL) and dried, concentrated to give the compound, 35i-b, (52.6g, 93percent) as colorless oil. NMR (300 MHz, CDCI3) δ 1.24-1.29 (m, 3H), 3.58 (s, 2H), 4.1 1-4.19 (m, 2H), 7.18-7.25 (m, 2H), 7.38-7.44 (m, 2H). LC-MS (M+H)+ 243, 245.
Reference: [1] Patent: WO2013/43624, 2013, A1, . Location in patent: Page/Page column 99
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  • [ 14062-30-7 ]
YieldReaction ConditionsOperation in experiment
98% for 20 h; Reflux Preparation of ethyl 3-bromophenylacetate: 2.5 ml of conc. sulphuric acid were added to a solution of 25 g (116 mmol) of 3-bromophenylacetic acid in 170 ml of ethanol.
The mixture was heated under reflux for 20 h.
After cooling, the mixture was concentrated under reduced pressure and the residue was dissolved in 800 ml of ethyl acetate.
The organic phase was washed three times with in each case 50 ml of saturated aqueous sodium bicarbonate solution and twice with in each case 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and, after filtration, concentrated under reduced pressure.
The residue obtained in this manner was purified by column chromatography on silica gel using the mobile phase hexane/0-20percent ethyl acetate.
This gave 27.8 g (98percent of theory) of ethyl 3-bromophenylacetate.
Preparation of the Title Compound:
97% at 0℃; for 2 h; Reflux Into a 250-mL round-bottom flask, were placed 2-(3-bromophenyl)acetic acid (5 g, 23.25mmol, 1 .00 equiv), ethanol (80m l_). This was followed by the addition of thionyl chloride (5.6 g, 46.28mmol, 2.00 equiv) dropwise with stirring at 0°C. The resulting solution was heated to reflux for 2 h. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated. This resulted in 5.5 g (97percent) of ethyl 2-(3-bromophenyl)acetate as colorless oil.
95% at 80℃; Compound I: Synthesis using modified procedure of Sonogashira: Step i: To a solution/suspension of 3-bromophenylacetic acid (5.02g, 23.33 mmol) in ethanol (100 ml.) at room temperature was added concentrated sulfuric acid (1mL). The colorless solid was then stirred overnight at 8O0C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated. The aqueous layer was extracted with 2 x ethyl acetate (25 mL) and brine (20 mL). The combinated organic layers were washed with 2 x saturated solution of NaHCO3 (25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95percent). 1H-NMR (400 MHz, CDCI3): δ 1.26 (t, J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1H)1 7.44 (d, J = 1.56 Hz, 1 H).
95% at 80℃; Example 1: Detailed experimental procedures for the preparation of the sodium salt of 3-pentylphenylacetic acid (hereinafter Compound I)Instrumentation:[00108] All HPLC chromatograms and mass spectra were recorded on an HP 1100 LC-MS Agilent instrument using an analytical C18 column (250 x 4.6 mm, 5 microns) with a gradient over 5 min of 15-99percent CH3CN-H2O with 0.01percent TFA as the eluant and a flow of 2 mL/min.Compound I: Synthesis using modified procedure of Sonogashira:Step i:[00109] To a solution/suspension of 3-bromophenylacetic acid (5.02g, 23.33 mmol) in ethanol (100 ml_) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solid was then stirred overnight at 8O0C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 ml_), water (25 mL) and the two layers were separated. The aqueous layer was extracted with 2 x ethyl acetate (25 mL) and brine (20 mL). The combinated organic layers were washed with 2 x saturated solution of NaHCO3 (25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95percent). 1H-NMR (400 MHz, CDCI3): δ 1.26 (t, J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1H), 7.44 (d, J = 1.56 Hz, 1H).
95% at 20 - 80℃; [0088] Step 1 : To a solution/suspension of 3-bromophenylacetic acid (5.02 g, 23.33 mmol) in ethanol (100 mL) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solution was then stirred overnight at 80°C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2 χ 25 mL) and brine (20 mL). The combinated organic layers were washed with saturated solution of NaHC03 (2 χ 25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95percent). 1H-NMR (400 MHz, CDCI3): δ 1.26 (t J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1 H), 7.44 (d, J = 1.56 Hz, 1 H).
95% at 80℃; [00100] To a solution/suspension of 3-bromophenylacetic acid (5.02 g, 23.33 mmol) in ethanol(100 mL) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solidwas then stirred overnight at 80°C. The solution was concentrated under reduced pressure. Theresidue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated.The aqueous layer was extracted with ethyl acetate (2 x 25 mL) and brine (20 mL). Thecombinated organic layers were washed with saturated solution of NaHCO3 (2 x 25 mL), brine(25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness.This gave a light yellow oil (5.4 g, 95percent). 1H-NMR (400 MHz, CDCI3): ö 1.26 (t, J = 4.7 Hz, 3H),3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1H), 7.44 (d, J =1.56 Hz, IH).
95% at 80℃; To a solution/suspension of 3-bromophenylacetic acid (5.02 g, 23.33 mmol) in ethanol (100 mL) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solid was then stirred overnight at 80°C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2 χ 25 mL) and brine (20 mL). The combinated organic layers were washed with saturated solution of NaHC03 (2 x 25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95percent). 1H-NMR (400 MHz, CDCIa): δ 1.26 (t, J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1 H), 7.44 (d, J = 1.56 Hz, 1 H).
93.4% at 0 - 20℃; for 5.08333 h; 74 lStep 1. HCl is bubbled through a solution of 3-bromophenyl acetic acid (10.5 g, 46.5 mmol) in EtOH (70 mL) chilled at O0C for 5 minutes. The flask is capped and stirred at ambient temperature for 5 hours. The mixture is concentrated. The residue is taken up with water (80 mL) and extracted twice with EtOAc (70 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford (3-bromo-phenyl)-acetic acid ethyl ester [10.55 g, 93.4percent] as an oil, which is used without further purification.
93.4% at 0 - 20℃; for 5.08333 h; HCl is bubbled through a solution of 3-bromophenyl acetic acid (10.5 g, 46.5 mmol) in EtOH (70 mL) chilled at O0C for 5 minutes. The flask is capped and stirred at ambient temperature for 5 hours. The mixture is concentrated. The residue is taken up with water (80 mL) and extracted twice with EtOAc (70 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford f3-bromo-phenyl)-acetic acid ethyl ester [10.55 g, 93.4percent] as an oil, which is used without further purification.
93% Reflux 3-Bromophenylacetic acid, 35i-a, (50g, 0.23mol) was dissolved in ethanol (250 mL) and sulfuric acid was added drop-wise. The mixture was heated to reflux and stirred overnight. The solution was adjusted to about a pH of 7-8 with sodium hydroxide solution and concentrated in vacuo. The water phase was extracted with ethyl atetate (3 x 150 mL) and the combined organics was washed with brine (50 mL) and dried, concentrated to give the compound, 35i-b, (52.6g, 93percent) as colorless oil. 1H NMR (300 MHz, CDCI3) δ 1.24-1.29 (m, 3H), 3.58 (s, 2H), 4.11-4.19 (m, 2H), 7.18-7.25 (m, 2H), 7.38-7.44 (m, 2H). LC-MS (M+H)+243, 245
93.4% at 0 - 20℃; for 5.08333 h; HCl is bubbled through a solution of 3-bromophenyl acetic acid (10.5 g, 46.5 mmol) in EtOH (70 mL) chilled at O0C for 5 minutes. The flask is capped and stirred at ambient temperature for 5 hours. The mixture is concentrated. The residue is taken up with water (80 mL) and extracted twice with EtOAc (70 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford f3-bromo-phenyl)-acetic acid ethyl ester [10.55 g, 93.4percent] as an oil, which is used without further purification.
88% at 0 - 85℃; Example A6; N-[(1-[3-[8-methyl-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-2-yl]phenyl]-1-methylethyl]amine; A6.1 tert-butyl 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamate; A6.1a: Ethyl 2-(3-bromophenyl)acetate; Commercially available 2-(3-bromophenyl)acetic acid (13 g 0.06 mol) was dissolved in ethanol (130 ml) and cooled to 0° C. Thionyl chloride (20 ml) was added drop wise. The mixture was heated to 85° C. over night. Reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 10percent NaHCO3, water, dried over anhydrous sodium sulfate and concentrated to give 13 g (88percent) of A6.1a.
88% at 20 - 80℃; for 15 h; To an ice cooled solution of 2-(3-bromophenyl)acetic acid (1 g, 4.6 mmol) in EtOH (10 mL), thionyl chloride (0.67 mL, 9.3 mmol) was added dropwise. The reaction mixture was then warmed to room temperature heated at 80° C. for 15 h. The reaction was monitored by TLC and after completion of the reaction, the reaction mixture was concentrated under vacuo and water was added to the residue. A saturated aqueous solution of NaHCO3 was added to the solution until the pH of the solution was 9. Then, the aqueous solution was extracted with EtOAc, the organic layer was dried over Na2SO4, concentrated under vacuum, and purified by column chromatography (silica gel) to yield ethyl 2-(3-bromophenyl)acetate yield 1.13 g. (88percent).
11.1 g for 3 h; Reflux To a solution of 2-(3-bromophenyl)acetic acid 1103 (10.0 g, 46.5 mmol) in 100 mL EtOH was added cone. H2S04 (10 drops) and the mixture heated to relux temperature for 3 hours. The mixture was allowed to cool to room temperature and the volatiles were removed under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with water (2 x 50 mL), saturated NaHC03 (1 x 25 mL), brine (2 x 25 mL) and dried over Na2S04. The Na2S04 was removed by filtration and the volatiles removed under reduced pressure to give ethyl 2-(3-bromophenyl)acetate 1097 (11.1 grams) as a liquid). 1H NMR 300 MHz CDC13: δ 7.41 (m, 2 H), 7.20 (m, 2H), 4.14 (q, 2H, J= 9.5 Hz), 3.57 (s, 2H), 1.25 (t, 3H, J= 9.5 Hz).

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YieldReaction ConditionsOperation in experiment
100% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; To dichloromethane (580 ml) solution of 25 g (116 mmol) of 3-bromophenylacetic acid were added 9.4 ml (232 mmol) of methanol and 0.15 g (1.2 mmol) of 4-(dimethylamino)pyridine. After cooling with ice, 26.8 g (140 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added thereto, and the resulting mixture was stirred overnight with gradually warming up to room temperature. The reaction mixture was washed with hydrochloric acid, saturated sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. After filtrating and concentrating under reduced pressure, 27.3 g (quantitative) of the entitled compound was obtained as a pale yellow oil.1H-NMR(CDCl3)δ: 3.60(2H, s), 3.70(3H, s), 7.16-7.23(2H, m), 7.39-7.45(2H, m).
100% Heating / reflux A mixture of 3-bromophenylacetic acid (5.29 g, 24.6 mmol) and concentrated sulfuric acid (100 μL) in anhydrous methanol (40 mL) was refluxed overnight and then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo to give 121A (5.82 g, 100percent) as pale yellow oil. LC-MS m/z: 228.18 (M+H)+.
99% for 2 h; Reflux INTERMEDIATE 6(3-BromophenyDacetic acid methyl ester Acetyl chloride (0.5 niL) was added to MeOH (100 mL). 3-Bromophenylacetic acid (15 g, 69.8 mmol) was added, and the mixture refluxed for 2 h. The solvent was removed in vacuo and the residue partitioned between DCM and water (50 mL each). The aqueous phase was extracted with DCM (20 mL) and the combined organic phases were dried (MgSO4) and the solvent removed in vacuo to give the title compound (15.85 g, 99percent) as a colourless oil. δH (CDCl3) 7.44 (s, IH), 7.37-7.43 (m, IH), 7.15-7.24 (m, 2H), 3.70 (s, 3H), 3.59 (s, 2H).
98% Heating / reflux To a solution of 3-bromophenylacetic acid (1 g, 4.65 mmol) in 20 mL MeOH at 0° C. was added thionyl chloride (0.51 mL, 1.5 eq.) dropwise. The resulting solution was then refluxed overnight under N2. The reaction was cooled to rt and the solvent was removed in vacuo. The residue was taken up in EtOAc, washed with sat'd. NaHCO3 and brine, then dried over Na2SO4, filtered and evaporated to provide the methyl ester in 98percent yield. 1HNMR (300 MHz, CDCl3) δ 7.57 (d, 1H, J=12 Hz); 7.29 (2H, dd, J=2.5, 0.8 Hz); 7.16 (m, 1H); 3.81 (s, 2H); 3.72 (s, 3H).
98.7% for 2 h; Reflux Acetyl chloride (0.08 mL, 1.2 mmol, 0.5 equiv), and 2-(3-bromophenyl)acetic acid (0.5 g, 2.3 mmol, 1.0 equiv) were added to MeOH (10 mL) and the reaction mixture was refluxed for 2 h. After consumption of starting material, the reaction mixture was concentrated and extracted with DCM. The organics were combined and washed with brine and dried over Na2S04, filtered and concentrated in vacuum to give methyl 2-(3-bromophenyl)acetate as colorless oil (0.525 g, 98.7percent). LC-MS (ES) m/z = 229.0, 231.0 [M+H]+ . H NMR (400 MHz, DMSOd6) δ 3.61 (s, 3 H), 3.70 (s, 2 H), 7.26 - 7.30 (m, 2 H), 7.43 - 7.46 (m, 1 H), 7.48 (s, 1 H).
97% at 10 - 20℃; for 2 h; a) Synthesis of methyl(3-bromophenyl)acetate25.00 g of (3-bromophenyl)acetic acid are dissolved in 80 ml of methanol in a 100 ml flask provided with magnetic stirrer, condenser, thermometer, dropping funnel and gas-discharge tube, 13.22 ml of thionyl chloride are added dropwise at max. 10° C. with cooling and stirring, and the mixture is subsequently stirred at RT for a further 2 h. The reaction mixture is poured onto ice, rendered alkaline using conc. sodium hydroxide solution and extracted with MTB ether. The combined MTB ether phases are dried and filtered. The solvent is subsequently removed.Yield: 25.44 g=0.111 mol=97percent of methyl(3-bromophenyl)acetate; TLC: CH2Cl2=100; Rf about 0.9; HPLC: RT=2.43 min.
97% at 10 - 20℃; for 2 h; a)
Synthesis of methyl (3-bromophenyl)acetate
25.00 g of (3-bromophenyl)acetic acid are dissolved in 80 ml of methanol in a 100 ml flask provided with magnetic stirrer, condenser, thermometer, dropping funnel with gas-discharge tube, 13.22 ml of thionyl chloride are added dropwise with cooling and stirring at max.
10° C., and the mixture is subsequently stirred at RT for a further 2 h.
The reaction mixture is poured onto ice, rendered alkaline using concentrated sodium hydroxide solution and extracted with MTB ether.
The combined MTB ether phases are dried, filtered and stripped off to dryness.
Yield: 25.44 g=0.111 mol=97percent of methyl(3-bromophenyl)acetate;
TLC: CH2Cl2=100; Rf approx. 0.9
HPLC: RT=2.43 min.
96% With hydrogenchloride In water at 20 - 58℃; for 2 h; 3-BROMOPHENYLACETIC acid (10000 mg, 46. 50MMOL) was dissolved in methanol (200 mL) at room temperature and concentrated hydrochloric acid (4 mL) was added. The resulting solution was heated at 58°C for 2h then cooled to room temperature at which time the volatiles were removed in vacuo. The crude material was dissolved in ethyl acetate and the solution was carefully poured into a saturated aqueous sodium bicarbonate solution. The phases were separated and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (Biotage) with a gradient of 4 to 35percent ACOET/HEXANES to give (3-bromo-phenyl)-acetic acid methyl ester as a colorless oil (10250 mg, 96percent). GC- MS (MH+ 230 RT = 9.34 min).
96% at 0 - 25℃; for 5 h; Acetyl chloride (0 7ml, 9 3mmol) was added dropwise to a solution of (3-bromo-phenyl)-acetic acid (20 Og, 93mmol) in methanol (500ml) at 0°C The reaction was stirred for 5 hours, allowing the temperature to warm gradually to 25°C The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless oil in 96percent yield, 20 6g1H NMR (400MHz, CDCI3) δ 3 59 (s, 2H) 3 70 (s, 3H), 7 24-7 17 (m, 2H), 7 37-7 45 (m, 2H), LRMS ESI m/z 253 [M+Na]+
96% at 20℃; Intermediate 2. (3-Bromo-phenyl)-acetic acid methyl ester. <n="19"/>[0056] Step A: 3-Bτomophenyl acetic acid (1.17 g, 5.44 mmol) is dissolved inMeOH (15 tnL) containing catalytic amounts of thionyl chloride (0.2 tnL). The solution is stirred at room temperature overnight. The solvent is evaporated, the remainder is dissolved in DCM and washed with water and saturated aqueous NaHCO3- The organic layer is dried (MgSO4), filtered and concentrated to afford the methyl ester 16 (1.20 g, 5.28 mmol, 96percent) as an oil: 1H-NMR (400MHz, CDCl3) δ = 7.44 (s, IH), 7.40 (ddd, J = 2.0, 2.4, 6.8 Hz, IH), 7.20 (m, 2H), 3.70 (s, 3H), 3.59 (s, 2H). MS calcd. for C9Hi0BrO2 (M+H"1") 229.1, found 229.0.
95% Reflux 3-Bromophenylacetic acid (100 g, 0.47 mol) was dissolved in methanol (1000 ml) and concentrated sulfuric acid (1 ml) added and the mixture heated at reflux overnight.
The methanol was evaporated and the residue partitioned between dichloromethane (600 ml) and saturated aqueous sodium bicarbonate (200 ml).
The organic layer was washed with brine (300 ml), dried over magnesium sulfate and concentrated to give methyl 2-(3-bromophenyl)acetate (102 g, 0.45 mol, 95percent) as an oil.
1H NMR (400 MHz, CDCl3): δ ppm 7.43 (bt, 1H), 7.38 (dt, 1H), 7.15-7.19 (m, 2H), 3.68 (s, 3H), 3.58 (s, 2H)
95% for 5 h; Dean-Stark; Reflux 2- (3-bromophenyl) acetic acid (1.00 g, 4.65 mmol) was dissolved in freshly distilled methanol (50 ml.) . Added cone. H2S04 (8 drops) and refluxed in a Dean-Stark apparatus for 3 hrs. Reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was dissolved in CH2C12 (40 mL) and washed with sat. NaHC03 (30 mL x 2) and sat. NaCl (30 mL) . The organic layer was dried (anhydrous sodium sulfate) and concentrated in vacuo. The crude product was chromatographed on silica gel (Hexanes/EtOAc, 5:1) to yield target compound 73. Yield 1.011 g, 95percent. Rf = 0.60, H NMR (400 MHz, Chloroform-d) δ 7.47 - 7.43 (m, 1H) , 7.41 (dt, J = 6.5, 2.2 Hz, 1H) , 7.24 - 7.16 (m, 2H) , 3.70 (s, 3H) , 3.60 (s, 2H) ; [M+H]+ = 230.12 (APCI+) .
94% at 0 - 80℃; for 3 h; [0180] To a solution of 2-(3-bromophenyl)acetic acid (5.0 g, 23.3 mmol) in CH3OH (30 mL), was added SOCl2 (3.2 g, 27.0 mmol) at 0 °C. Then the mixture was stirred at 80 °C for 3 hours. The solvent was removed under reduced pressure to give methyl 2-(3- bromophenyl)acetate (5.0 g, yield: 94percent); LC/MS: m/z (M++l) = 231.
91% at 40℃; for 16 h; Example 18; Preparation of Methyl (3-Bromophenyl)acetateA stirred solution of (3-bromophenyl)acetic acid (10.0 g, 0.0465 mol) and concentrated sulfuric acid (4.5 mL) in MeOH (230 mL) was heated at 40 0C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was mixed with water (50 mL) and DCM (100 mL). The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10percent EtOAc/hexanes) to give the title compound (19.8 g, 91 percent yield) as a colorless oil.LC-MS (Method 10-90): Rt 3.36 min; mlz 300.4 [M + H]+; 229.6 [M+]. 1H NMR (CD3OD) δ 7.48(s, IH); 7.44(d, IH); 7.26-7.25(m, 2H); 3.71(s, 3H); 3.66(s, 2H).
90% for 3 h; Reflux Step 1 : [00152] To a solution of (3-bromophenyl)acetic acid (12.2 g, 56.8 mmol) in methanol (150 ml_) was added p-toluenesulfonic acid (5.4 g, 28.4 mmol). The reaction mixture was stirred at reflux for 3 hours. The solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate/water (3:2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified using a silica pad eluting with a mixture of hexanes/ethyl acetate (9:1). This gave (3-bromophenyl)acetic acid methyl ester as a colorless oil (11.7 g, 90percent). 1H NMR (400 MHz, CD3OD): δ = 7.46 (m, 1 H), 7.41 (m, 1 H), 7.22 (m, 2H), 3.68 (s, 3H)1 3.65 (s, 2H); LRMS (ESI): m/z = 229 (MH+); HPLC: 3.8 min.
90% for 3 h; Reflux [0095] Step 1 : To a solution of (3-bromophenyl)acetic acid (12.2 g, 56.8 mmol) in methanol(150 mL) was added p-toluenesulfonic acid (5.4 g, 28.4 mmol). The reaction mixture was stirred at reflux for 3 h. The solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate/water (3:2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified using a silica pad eluting with a mixture of hexanes/ethyl acetate (9:1 ). This gave (3- bromophenyl)acetic acid methyl ester as a colorless oil (1 1.7 g, 90percent). 1H NMR (400 MHz, CD3OD): δ = 7.46 (m, 1 H), 7.41 (m, 1 H), 7.22 (m, 2H), 3.68 (s, 3H), 3.65 (s, 2H); LRMS (ESI): m/z = 229 (MH+); HPLC: 3.8 min.
86.1% Reflux Methyl 2-(3-bromophenyl) acetateBrTo the solution of the starting material (12.0 g, 55.8 mmol) in MeOH (200 mL) wasadded SOCI2(2 mL). The reaction solution was stirred and heated to reflux overnight.After the reaction was completed, 200mL of water and 30 mL of NaHCO3 aq. were added. The mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over Na2504. After filtration and evaporation of the solvent, the product (11 .Og, 86.1 percent) was obtained.
86.1% Reflux To the solution of the starting material (12.0 g, 55.8 mmol) in MeOH (200 mL) was added SOCI2 (2 mL). The reaction solution was stirred and heated to reflux overnight. After the reaction was completed, 200mL of water and 30 mL of NaHCOs aq. were added. The mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, the product (1 1 . Og, 86.1 percent) was obtained.
4.9 g With hydrogenchloride In water for 3 h; Reflux (3-Bromophenyl)acetic acid 11 (5.0 g, 23.3 mmol) and methanol (50 mL) were refluxed for 3 h in the presence of 0.2 mL of concentrated hydrochloric acid (HCl) to give the methyl (3-bromophenyl)acetate. After neutralization with saturated NaHCO3 and washing with brine, a pure product was obtained from the diethyl ether extract. This methyl acetate (4.9 g, 21.4 mmol) in dry THF (35 mL) was added dropwise to a stirred solution of 2.0 mol/L lithium diisopropylamide (LDA) (12.9 mL, 25.8 mmol) in THF/ethylbenzene/heptane at -78 °C under argon (Ar), and after 30 min, iodomethane (CH3I) (2.0 mL, 32.2 mmol) was added slowly. The resulting solution was stirred for 5 h with the temperature changed from -78 to -40 °C, then evaporated to dryness, and extracted with CH2Cl2 (50 mL). Evaporation of the solvent and purification of the residue by silica gel chromatography (n-hexane/AcOEt, 20:1) yielded the title compound as a colorless liquid (77.2percent). 1H NMR (CDCl3) δ: 1.49 (3H, d, J = 7.1 Hz, α-CH3), 3.67 (3H, s, CO2CH3), 3.68 (1H, q, J = 7.1 Hz, CH), 7.18 (1H, t, J = 7.5 Hz, Ar-H5), 7.23 (1H, dt, J = 7.8, 1.7 Hz, Ar-H6), 7.38 (1H, dt, J = 7.3, 1.8 Hz, Ar-H4), 7.44 (1H, st, J = 1.7 Hz, Ar-H2). FAB-MS (m/z): 243.02 (M++H, calcd for C10H1279BrO2: 243.00).
1.97 g at 0℃; for 2 h; Reflux Example 5A: Methyl 2-(3 -bromophenyl)acetate j00225j 3-Bromophenylacetic acid (2.0 g, 9.30 mmol) was dissolved in MeOH (46.5mL) and cooled to 0 °C. SOC12 (3.39 mL, 46.5 mmol) was added carefully dropwise.The reaction was then heated to reflux at for 2 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 to 100percent EtOAc in hexanes to yield Example 5A (1 .97g, 8.60 mmol). 1H NMR (400 MHz, CHLOROFORM-cl) ö ppm 7.44 (1 H, s), 7.36 - 7.43 (1 H, m), 7.15 -7.24 (2 H, m), 3.70 (3 H, s), 3.60 (2 H, s).

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[52] Patent: WO2005/113519, 2005, A1, . Location in patent: Page/Page column 47-48
[53] Patent: WO2008/39882, 2008, A1, . Location in patent: Page/Page column 201
  • 32
  • [ 1878-67-7 ]
  • [ 150529-73-0 ]
YieldReaction ConditionsOperation in experiment
100% With sulfuric acid In methanol for 3 h; Heating / reflux Step (v); Methyl 3-bromophenylacetate; [Show Image] To 3-bromophenylacetic acid 10.0g (46.5mmol) were added methanol 150ml and sulfuric acid 5ml and the mixture was refluxed for 3 hours. After neutralization with aqueous ammonia and removal of the solvent by distillation, to the residue was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography (SiO2 200g, eluent: Hexane/EtOAc=6/ 1) to give the object compound 10.65g as a colorless oil. Quantitatively 1H NMR (CDCl3) δ 7.44 (1H, s), 7.41 (1H, m), 7.21 (2H, m), 3.71 (3H, s), 3.60 (2H, s).
99% With sulfuric acid In methanol; dichloromethane; ethyl acetate Part A
3-Bromophenyl acetic acid (2.0 g, 9.3 mmol) was dissolved in methanol (20 ml) in a 50 ml flask.
Concentrated sulfuric acid (2 drops) was added, and the mixture was refluxed under nitrogen for ten hours then concentrated under reduced pressure.
The residue was mixed with dichloromethane (20 ml) and saturated sodium bicarbonate solution (10 ml).
The organic material was separated, dried (MgSO4) and concentrated under reduced pressure.
The residue was flushed through silica gel with hexane/ethyl acetate (3:1), and concentrated to provide 2.12 g (99percent) of methyl (3-bromophenyl)acetate, which was used without further purification.
Reference: [1] Patent: EP1939202, 2008, A1, . Location in patent: Page/Page column 41
[2] Patent: US6518267, 2003, B1,
[3] Patent: US5444050, 1995, A,
[4] Patent: WO2006/44732, 2006, A2, . Location in patent: Page/Page column 202
[5] Patent: US2005/80111, 2005, A1,
[6] Angewandte Chemie - International Edition, 2012, vol. 51, # 2, p. 548 - 551
[7] Patent: WO2004/108676, 2004, A1, . Location in patent: Page 129-130
  • 33
  • [ 1878-67-7 ]
  • [ 18107-18-1 ]
  • [ 150529-73-0 ]
Reference: [1] Patent: US2003/171377, 2003, A1,
[2] Patent: US6939861, 2005, B2,
[3] Patent: US2003/199458, 2003, A1, . Location in patent: Page/Page column 48
  • 34
  • [ 1878-67-7 ]
  • [ 75-36-5 ]
  • [ 150529-73-0 ]
Reference: [1] Patent: EP1477167, 2004, A1, . Location in patent: Page/Page column 43
  • 35
  • [ 1878-67-7 ]
  • [ 74-88-4 ]
  • [ 150529-73-0 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2011, vol. 59, # 12, p. 1523 - 1534
  • 36
  • [ 186581-53-3 ]
  • [ 1878-67-7 ]
  • [ 150529-73-0 ]
Reference: [1] Patent: US2002/65230, 2002, A1,
[2] Patent: US5998470, 1999, A,
  • 37
  • [ 1878-67-7 ]
  • [ 364793-86-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3018 - 3022
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
  • 38
  • [ 1878-67-7 ]
  • [ 364794-82-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
  • 39
  • [ 1878-67-7 ]
  • [ 478375-42-7 ]
Reference: [1] Patent: US2011/257172, 2011, A1,
[2] Patent: US2011/257173, 2011, A1,
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 22, p. 7815 - 7833
  • 40
  • [ 1878-67-7 ]
  • [ 71420-95-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2647 - 2652
  • 41
  • [ 1878-67-7 ]
  • [ 81606-47-5 ]
Reference: [1] Patent: WO2008/39882, 2008, A1,
  • 42
  • [ 1878-67-7 ]
  • [ 75-65-0 ]
  • [ 197792-52-2 ]
Reference: [1] Molecules, 2010, vol. 15, # 3, p. 1590 - 1631
[2] Patent: WO2016/198374, 2016, A1, . Location in patent: Page/Page column 123-124
  • 43
  • [ 1878-67-7 ]
  • [ 197792-52-2 ]
YieldReaction ConditionsOperation in experiment
72% With trifluoroborane diethyl ether; sodium hydrogencarbonate In dichloromethane; cyclohexane Preparation D
(3-Bromo-phenyl)-acetic acid tert-butyl ester:
To a solution of 3-bromo-phenyl-acetic acid (10 gm, 46.5 mmol) and methylene chloride (47 mL) was added a solution of t-butyl-2,2,2-trichloroacetamidate (20.3 g, 93.0 mmol) and cyclohexane (186 mL) followed by borontrifluoride etherate (0.93 mL, 7.3 mmol).
After stirring overnight, solid sodium bicarbonate was added and the reaction then filtered through a pad of silica gel utilizing methylene chloride as solvent.
Concentration gave 9.11 g (72percent) of a colorless oil.
1H-NMR (CDCl3, δ): 1.41 (s, 9H), 3.46 (s, 2H), 7.1-7.4 (multiplets, 4H).
Reference: [1] Patent: US6576632, 2003, B1,
  • 44
  • [ 24424-99-5 ]
  • [ 1878-67-7 ]
  • [ 75-65-0 ]
  • [ 197792-52-2 ]
Reference: [1] Patent: WO2007/87448, 2007, A1, . Location in patent: Page/Page column 40
  • 45
  • [ 1878-67-7 ]
  • [ 1198615-70-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6608 - 6612
[2] Patent: US2012/295874, 2012, A1,
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